Protein kinase is the largest family of human kinase and contains over 500 proteins. Spleen tyrosine kinase (Syk) is a member of Syk family of tyrosine kinase, and is a regulator for the development of B cells at early stage. Syk also regulates the activation, signal transduction and lifespan of mature B cells.
Syk is a non-receptor tyrosine kinase which plays a critical role in immunoreceptor and integrin-mediated signal transduction in various cells including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T cells, natural killer cells, thrombocytes and osteoclasts. The immunoreceptors described herein include typical immunoreceptors and molecules similar to immunoreceptors. Typical immunoreceptor includes B cells, T cell antigen receptors and various immunoglobulin receptors (Fc receptor). Molecules similar to immunoreceptors may relate to a structure of the immunoreceptor, or may participate in a similar signal transduction pathway with the typical immunoreceptor. Also, these molecules mainly take part in nonadaptive immune response such as activation of neutrophils, natural killer cell recognition and osteoclast activity. Integrin is a cell surface receptor which plays a critical role in leukocyte adhesion and activation, in both congenital immunity and adaptive immunity.
Binding of the ligand activates both immunoreceptor and integrin, and results in a phosphorylation of an immunoreceptor tyrosine-based activation motif (ITAM) in cytoplasmic surface of a receptor associated transmembrane adaptin. The activation activates Src family kinase. Syk combines with the phosphorylated ITAM of an adaptin to tirgger Syk activation and the subsequent phosphorylation and downstream signaling pathway activation.
Syk is essential to the activation of B cells by B cell receptor (BCR) signal transduction. Syk is activated when binding to the phosphorylated BCR. Thereby, early signal transduction event occurs after BCR activation. The B cell signal transduction through BCR may result in a wide range of biological yield, which depends on the stage of development of B cells. The magnitude and duration of a BCR signal have to be regulated accurately. Abnormal BCR-mediated signal transduction could cause disordered B cell activation and/or result in production of autoantibodies causing multiple-autoimmune diseases and/or inflammatory diseases. Syk-deficient mice show impaired mature B cells, reduced production of immunoglobulin, compromised T cell irrelevant immune response, and significant degradation of persistent calcium signal in BCR stimulation.
Functions of B cells and humoral immune system in etiology of autoimmunity and/or inflammatory disease have been evident with substantial proofs. A protein-based therapy (such as Rituxan) developed for complete depletion of B cells provides an approach for treating many autoimmune diseases and inflammatory diseases. It is known that the autoantibodies and the immune complex produced therefrom function as a pathogen in autoimmune diseases and/or inflammatory diseases. Pathogenic responses on these antibodies rely on a signal transduction through a Fc receptor which depends on Syk. Since Syk is involved in B cell activation and FcR dependent signal transduction, an inhibitor of Syk can thus be used as an inhibitor for inhibiting B cell-mediated pathogenic activity which is caused by autoantibodies. Therefore, it is suggested that the suppression of Syk enzyme activity in cells exerts effect on autoantibodies and thus can be used for treating autoimmune disease.
Syk also plays a pivotal role in FcεRI-mediated mast cell degranulation and activation of eosinophils. Therefore, Syk is also involved in allergic disorder such as asthma. Syk binds to the phosphorylated Y chain of FcεRI through its SH2 domain. Syk is necessary for downstream signal transduction. Syk-deficient mast cells show impaired degranulation, arachidonic acid and cytokine secretions. Therapeutic agents used for suppressing Syk activity in mast cells also show the above conditions. The therapy using Syk antisense oligonucleotide suppresses permeation of antigen induced eosinophils and neutrophils in asthma animal model. Syk-deficient acidophil cells also show impaired activation because of response to FcεRI stimulation. Therefore, small molecule inhibitors for inhibiting Syk are useful for treating allergy-induced inflammatory diseases such as asthma.
Syk is also very important to the functions of mast cells and mononuclear cells. For example, Syk deficiency in mice is related to the impaired IgE-mediated mast cells activation. The IgE-mediated mast cells activation significantly reduces the release of TNFα and other inflammatory cytokines. Also, it is shown that Syk kinase inhibitor suppresses mast cell degranulation in cell-based analysis. In addition, it has been shown that Syk inhibitor suppresses antigen-induced Passive Cutaneous Anaphylaxis (PCA), bronchoconstriction and bronchoedema in rats.
Therefore, the suppression of Syk activity can be used for treating and/or preventing Syk-associated diseases. Specifically, the suppression of Syk activity can be used for treating allergic disorders, autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple polyangitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS) and asthma. In addition, Syk plays a key role in ligand-independent nourishing signal transduction, which is known to be important survival signal transduction in B cells. Thus, inhibition of Syk activity can be used for treating certain cancers including B cell lymphomas and leukemia.